Treatment Outcomes and Patterns of Failure
in Elderly Patients with Cervical Cancer Treated
with Definitive Radiotherapy
Received: September 23, 2020 Accepted: November 19, 2020 Online: November 27, 2020 Accessible online at: www.onkder.org
Gautam SARMA, Luri BORAH, Jyotiman NATH, Mouchumee BHATTACHARYYA, Partha Pratim MEDHI, Apurba Kumar KALITA
Department of Radiation Oncology, Dr. Bhubaneswar Borooah Cancer Institute, Guwahati, Assam-India
OBJECTIVE
The incidence of cervical cancer among older women is increasing. The treatment outcome in these patients is affected byvarious patient and tumor-related factors. In this study, we retrospectively investi-gated the survival outcomes, treatment-related toxicity, and patterns of failures for elderly patients (≥75 years old) with cervical cancer treated with definitive radiotherapy.
METHODS
Twenty-three patient’s fulfilling inclusion and exclusion criteria were analyzed. The survival was studied using the Kaplan-Meir method, and its relation with different clinicopathologic parameters was com-pared.
RESULTS
After a median follow-up time of 46 months (range 3-93), the overall survival for the entire cohort of patients at 5 years and 7 years were 54.9% and 43.9%, respectively, and the disease-free survival at 3 years and 5 years were 66.3% and 45.9% respectively. Patients receiving total radiation dose (EqD2) more than 80 Gy achieved statistically significant improved survival than those receiving lower doses (p=0.04). Grade III acute toxicity was experienced by 2 patients (8.7%) with diarrhea and one patient (4.3%) with dermatitis, but no grade IV acute toxicity was recorded. Two patients (8.7%) developed rectal bleeding as late toxicity. At the end of follow-up, 11 patients (47.8%) experienced a relapse. Distant metastasis to the lung was the most common type of failure.
CONCLUSION
Definitive radiotherapy is safe and well-tolerated by elderly patients with cervix cancer with an accept-able degree of toxicities.
Keywords: Cancer; cervix; chemotherapy; elderly; radiotherapy. Copyright © 2021, Turkish Society for Radiation Oncology
Dr. Jyotiman NATH
Department of Radiation Oncology, Dr. Bhubaneswar Borooah Cancer Institute, Guwahati, Assam-India
E-mail: jyotimannath@gmail.com OPEN ACCESS This work is licensed under a Creative Commons
Attribution-NonCommercial 4.0 International License.
of cancer-related morbidity worldwide. In India, it is the second most common cancer in women.[1,2] The incidence and mortality due to cervical cancer is de-clining in developed countries. This is primarily due
Introduction
Cervical cancer is the fourth most common malig-nancy in women and remains one of the leading causes Gautam SARMA https://orcid.org/0000-0002-2907-210X
Luri BORAH https://orcid.org/0000-0002-4600-3106 Jyotiman NATH https://orcid.org/0000-0002-4075-9631
Mouchumee BHATTACHARYYA https://orcid.org/0000-0002-5565-8200 Partha Pratim MEDHI https://orcid.org/0000-0002-3997-4350
to the increase of knowledge that persistent human papillomavirus (HPV) infection is the leading cause of cervical cancer, resulting in the development of prophylactic vaccines. However, it is still a significant health problem in developing countries due to the lack of routine screening and introduction of vacci-nation programs.[3,4]
Cervical cancer demonstrates a bimodal age dis-tribution, with peaks between 30 to 39 years and 60 to 69 years. Data from various hospital-based cancer reg-istries (HBCR) of India reports the mean age of pre-sentation ranging between 50 and 56.7 years. Patients above 65 years of age account for around 15% of these HBCRs. With the increase in life expectancy of the population, the incidence of cervical cancer among elderly women is increasing.[5,6] Elderly patients are heterogeneous to comorbidities, performance status, access to healthcare and motivation towards screen-ing programs, etc. These factors contribute to the de-layed diagnosis and compromised treatment of this age group?. Moreover, various reports have demon-strated that elderly women often present with more advanced staged disease and receive less aggressive treatment.[7,8]
There are conflicting reports on the impact of age on treatment outcome in cervical cancer. Many studies have reported age to be a prognostic factor in cervix cancer.[9-12] Some studies have shown a similar prog-nosis of cervical cancer in old and young women, while few demonstrated that younger age is an unfavorable prognostic factor.[13,14] However, there are kinds of literature which reported younger patients might have improved outcome and old age is a poor prognostic factor.[15-17]
In this study, we retrospectively analyzed the sur-vival outcomes, treatment-related toxicity, and patterns of failures for elderly women (≥75 years) with cervical cancer treated with definitive radiotherapy (RT) with or without concurrent chemotherapy (CCRT).
Materials and Methods
Patient Selection and Assessment
Cervical cancer patients treated between 2011 and 2015 in our institute were retrospectively reviewed. The inclusion criteria were as follows: age 75 years or more, histologically proven carcinoma of the cervix, patients treated with definitive radiotherapy, no prior history of surgery, chemotherapy or radiation for car-cinoma cervix, and no evidence of distant metastasis. Patients treated with palliative radiotherapy were
ex-cluded from the study. Twenty-three patients (n=23) fulfilling inclusion and exclusion criteria were included in the analysis.
The patients were staged according to the Inter-national Federation of Gynaecology and Obstetrics (FIGO-2009) staging system.[18] The findings of clin-ical examination notes, chest roentgenography, intra-venous pyelography, cystoscopy, and proctoscopy were used for staging. Patients’ baseline Eastern Cooperative Oncology Group (ECOG) performance status and co-morbidities were also recorded.
Treatment
All the patients received Radiotherapy with curative in-tent. The patients received external beam radiotherapy (EBRT) with a conventional technique. Patients were treated in a supine position using a thermoplastic pel-vic mould for immobilization. X-Ray simulation was done in Simulix Evolution (Nucletron) conventional simulator for treatment planning. EBRT was delivered using the four-field box technique with 6 MV photons in Elekta Precise digital linear accelerator (LA) and Sie-mens Primus LA. EBRT dose ranged between 46-50 Gy in 2Gy daily fractions. Three patients received concur-rent chemotherapy with weekly inj Carboplatin AUC 2 for 5 cycles.
EBRT was followed by high dose rate (HDR) in-tracavitary brachytherapy (ICBT) in Microselectron HDR (Nucletron, The Netherlands) using a 192-Irid-ium remote afterloading unit. Two patients did not receive brachytherapy as they defaulted after EBRT and one patient received EBRT boost as brachyther-apy could not be performed because of the stenosed vagina. Treatment planning for HDR-ICBT was per-formed using PLATO Brachytherapy Planning System version 3.2 (Nucletron, The Netherlands). Evaluation of the rectal and bladder dose was performed accord-ing to ICRU Report 38.[19] The dose of brachyther-apy was either 700cGy or 750 cGy to point A for 2 to 4 fractions.
Follow-up
After completion of treatment, the patients were fol-lowed up by both gynecological and radiation oncol-ogists. A gynecological examination was performed in each follow-up. Radiological investigations like computed tomography (CT) or magnetic resonance imaging (MRI) were performed as and when neces-sary.
Both acute and late treatment-related toxicities were evaluated using medical records and CTC-AE
(4.3%) had adenosquamous and one patient (4.3%) had small cell carcinoma histology. The FIGO stage of the patients ranged from IB2 to IVA. Stage IIB was most common (10 patients; 43.5%) followed by IIIB (8 patients; 34.8%), IVA (3 patients; 13%) and IB292 pa-tients; 8.7%) respectively. Twelve patients (52.2%) had medical comorbidities like diabetes or hypertension or both.
The patients received EBRT by a conventional treat-ment planning to a dose ranging from 46 to 50 Gy in 2Gy daily fractions with the four-field box technique. Twenty patients (86.9%) received HDR-ICBT. The brachytherapy dose was either 7 Gy or 7.5 Gy per frac-tion for 2-4 fracfrac-tions. One patient received an exter-nal beam boost of 14 Gy in 7 fractions as brachyther-apy could not be planned due to stenosed vagina and two patients (8.7%) defaulted and did not receive brachytherapy. Total brachytherapy dose (EqD2) was more than 30 Gy in 10 patients (43.5%) and less than 30 Gy in another 10 patients (43.5%). The overall du-ration of radiotherapy ranged from 42 to 70 days, with a median of 55 days. Fourteen patients (60.9%) com-pleted their entire course of treatment in less than 8 weeks. Only three patients (13%) received concurrent chemotherapy with weekly inj Carboplatin AUC 2 for 5 cycles.
Survival
The median follow-up time was 46 months (range 3-93). At the end, nine patients (39.1%) were alive. The overall survival (OS) for the entire cohort of pa-tients at 5 years and 7 years was 54.9% and 43.9% respectively and the disease-free survival (DFS) at 3 years and 5 years were 66.3% and 45.9%, respectively (Fig. 1).
The univariate analysis of various patient and treat-ment parameters influencing OS and DFS are shown in Table 2. The OS at 5 years and 7 years for the pa-tients with pre-treatment ECOG score 0-1 are superior to those with score 2-3, but the statistical difference only reached borderline significance (p=0.06). The patients of stage IB2-IIB had superior 5-year OS and DFS (66.7% and 46.3%) than of stage IIIB-IVA (41.6% and 44.4%); p=0.12 and 0.54 respectively. The patients of squamous cell carcinoma histology had statistically significant improved OS and DFS (Fig. 2) (p=0.009 and p<0.001 respectively).
The median total radiation dose (EqD2, 2 Gy equiv-alent dose) including, EBRT and ICBT of the patients was 79.75Gy (range 50-85.67). Nine patients (39.1%) received more than 80 Gy. The OS at 5 years of the pa-version 4.0. Toxicities occurring within 90 days of the
start of treatment were defined as acute, and those that occurred after 90 days persisted beyond 90 days of start of treatment were coined as late.
Statistical Analysis
Baseline variables were depicted as numbers (Percent-age). Kaplan Meir’s method was used to evaluate the survival rate, and the log-rank test was used to com-pare the survival among groups, and the t-test was used to compare two means. P<0.05 is considered as statis-tically significant at 95% confidence interval. All data were analyzed using IBM SPSS Statistics for Windows, version 21 (IBM Corp., Armonk, N.Y., USA).
Results
Patient Characteristics and Treatment
During the period 2011 to 2015, a total of 23 patients were eligible for the analysis. The baseline patient char-acteristics are depicted in Table 1. The median age was 77 years (range 75-85). The majority of the patients (19 patients, 82.6%) had squamous cell carcinoma. Two patients (8.7%) had adenocarcinoma; one patient
Table 1 Baseline patient characteristics
Patient Number of patients Percentage
characteristics (Total n=23) Age Median (Range) 77(75-85) 75-80 years 16 69.6% >80 years 7 30.4% PS (ECOG) 0 to 1 14 60.9% 2 to 3 9 39.1% Stage(FIGO) IB2 2 8.7% IIB 10 43.5% IIIB 8 34.8% IVA 3 13.0% Histology
Squamous cell carcinoma 19 82.6%
Adenocarcinoma 2 8.7% Adeno Squamous 1 4.3% Small cell 1 4.3% Medical co-morbidity Yes 12 52.2% No 11 47.8%
PS: Performance Score; (ECOG): Performance Score (Eastern Cooperative Oncology Group).
Fig. 1. Overall survival and disease-specific survival (OS and DSS) rates for all patients using the Kaplan–Meier method. Table 2 Comparison of survival among various patient and treatment-related factors
Variable No. of patients (%) Overall survival (OS) Disease-free survival (DFS)
5 Yrs (%) 7 Yrs (%) p 3Yrs (%) 5 Yrs (%) p
PS 0 to 1 14 (60.9%) 69.2 51.9 0.06* 64.3 42.9 0.6 2 to 3 9 (39.1%) 33.3 33.3 71.4 53.6 Stage IB2-IIB 12 (52.2%) 66.7 66.7 0.12 64.8 46.3 0.5 IIIB-IVA 11 (47.8%) 41.6 27.7 66.7 44.4 Histopathology SCC 19 (82.6%) 63.2 50.5 0.009* 81.6 56.5 <0.001* Others 4 (17.4%) 0 0 0 0
Total ICRT dose (EqD2)
Less than 30Gy 10 (43.5%) 40 40 0.2 46.7 23.3 0.1
30 Gy or more 10 (43.5%) 78.8 52.5 80 60
Not taken 3 (13.0%) 33.3 33.3 100 100
Total radiation dose (EqD2)
Less than 80 Gy 14 (60.9%) 35.7 35.7 0.04* 48.2 28.9 0.3
80 Gy or more 9 (39.1%) 87.5 58.3 88.9 66.7
Total treatment duration (Days)
56 or less 14 (60.9%) 62.3 62.3 0.2 76 59.1 0.03*
More than 56 9 (39.1%) 44 0 53.3 26.7
Concurrent chemotherapy
Yes 3 (13%) 66.7 66.7 0.5 33 0 0.04*
No 20 (87%) 53.1 42.5 72 54
8 (34.8%) and 4 (17.4%) patients respectively during treatment.
Two patients (8.7%) developed late rectal bleeding due to proctitis for which they had to undergo argon plasma photocoagulation. Only one patient (4.3%) within the entire cohort developed grade II lym-phedema of the bilateral lower limbs. Eleven patients (47.8%) developed varying grades of vaginal stricture including one patient (4.3%) with grade III. One pa-tient (4.3%) developed grade II cystitis and presented with moderate haematuria.
Patterns of Failure
Failure was defined as either recurrence of disease or persistent disease following radiotherapy. The failure was classified as 1. Locoregional: a residual or recur-rent disease at cervix or uterus and/or pelvic failures below L5–S1 level including nodal, parametrial, and vaginal; 2. Distant: systemic spread, supraclavicular, and/or inguinal spread; 3. PA nodes above L5–S1.
The patterns of failure are shown in Table 4. At the end of follow-up, 11 patients (47.8%) experienced a relapse. The details of various patterns of failure are shown in Table 4. Four patients (17.4%) had residual disease after treatment. The most common failure was distant metastases. Five patients (21.7%) had isolated tients receiving more than 80 Gy was superior to those
receiving lesser doses (87.5% vs 35.5% respectively; p=0.04) Figure 2. The patients completing the entire course of treatment, within 8 weeks had improved OS and DFS at 5 years (62.3% and 59.1% respectively) in comparison to those taking longer treatment time (44% and 26.7% respectively); p=0.2 and 0.03 respec-tively (Fig. 2). The three patients who received concur-rent chemotherapy had improvement of OS at 5 years than the others (66.7% vs 53.1%) but the difference is not statistically significant(p=0.5). However, no benefit was observed in terms of DFS in these patients receiv-ing concurrent chemotherapy with Carboplatin.
Treatment-Related Acute and Chronic Toxicities
The acute and chronic treatment-related toxicities are shown in Table 3. Thirteen patients (56.2%) experi-enced acute gastrointestinal toxicity. Grade III acute toxicity was experienced by two patients (8.7%) with diarrhea and one patient (4.3%) with dermatitis, but no grade IV acute toxicity was recorded. The patients experiencing grade II-III diarrhea were managed con-servatively with intravenous fluid and anti-diarrheal agents. Ten patients (43.5%) developed grade II der-matitis and only one patient (4.3%) developed grade III dermatitis. Grade I and II anemia were recorded in
a
c
b
d
Fig. 2. Comparison of OS and DFS among (a) FIGO stages (b) Histology, SCC vs. Others (c) total radiation dose, <80 Gy
disease (4 patients, 17.4%); but the difference is not sta-tistically significant (p=0.1).
Discussion
It is an inconclusive issue that whether the treatment outcomes of elderly patients with cervical cancer are poorer than their younger counterparts. Multiple ret-rospective series have shown mixed results in terms of treatment outcome and toxicity.[20-23]
In this study, we retrospectively reviewed the treat-ment outcome, toxicity, and patterns of failure of cervi-distant metastases and two patients (8.7%) had cervi-distant
metastases with locoregional failure. Among the dis-tant metastases, lung metastases were most common (4 patients, 17.4%) followed by bone metastases (3 pa-tients, 13%). Two patients (8.7%) developed para-aor-tic lymph nodes during the follow-up.
The patients who had failure received a lower mean total radiation dose (EqD2) in comparison to those without any relapse (73.46±12.66 Vs 79.88±6.55; p=0.1). Patients with stage IIIB-IVA (7 patients, 30.4%) experienced more failure than those with stage IB2-IIB
Table 4 Comparison of failure with various parameters
Treatment relapse Total Total dose (EqD2) Total treatment Stage
patients (23) (Mean±SD) duration (Mean±SD) IB2-IIB (n=12), (%) IIIB-IVA (n=11), (%)
No 12 79.88±6.55 55.58±4.80 8 (34.8) 4 (17.4) Yes 11 73.46±12.66 56.55±7.2 4 (17.4) 7 (30.4) P value 0.1 0.7 0.1 Relapse/failure No relapse 12 (52.2%) Relapse/failure 11 (47.8%) Type of failure/relapse Loco regional (LR) 2 (8.7%) Distant Mets 5 (21.7%) LR+Distant Mets 2 (8.7%) LR+Abdominal (PAN) 2 (8.7%) Types of Distant failure
Lung 4 (17.4%)
Bone 3 (13%)
PAN: Para-aortic node; SD: Standard deviation
Table 3 Acute and chronic treatment-related toxicities
Acute (%) Chronic (%)
Gastrointestinal (Diarrhoea) Gastrointestinal (Rectal bleeding)
NO 10 (43.5) Grade 2 2 (8.7)
Grade I 7 (30.4)
Gr II 4 (17.4) Lymphedema
Grade III 2 (8.7) Grade 2 1 (4.3)
Dermatitis
Grade I 12 (52.2)
Gr II 10 (43.5) Vaginal stenosis
Grade III 1 (4.3) No 12 (52.2)
Genitourinary (Urinary frequency) Grade I 7 (30.4)
Grade I 5 (21.7) Grade II 3 (13)
Grade II 2 (8.7) Grade III 1(4.3)
Haematological
Grade I 8 (34.8) Genitourinary (Cystitis)
cal cancer patients of 75 years or older treated with definitive radiotherapy. The age of 75 years or older was selected based on the defi-nition of “elderly” published in various cancer literature. [7,24-26]
The most relevant studies and guidelines recommend that the women with early-stage disease (FIGO stage IA-IB1/IIA1) are treated with surgery and those with locally advanced disease (FIGO stage IB2/ IIA2-IVA) with a combination of radiotherapy and chemo-therapy. But older patients are less likely to receive all types of standard treatments com-pared with the younger ones. Possible reasons include concerns regarding co-existing med-ical co-morbidities, lack of access to care, in-creased toxicity, and physician or patient pref-erence. Various literature have reported that elderly patients have treated less aggressively. [8,27-30]
Definitive radiotherapy is being consid-ered as one of the primary treatment modal-ity for elderly patients with cervical cancer. But compared to young patients, few elderly cervical cancer patients receive concurrent chemotherapy when treated with definitive radiotherapy.[31]
Despite the disparities in treatment, re-cent studies have demonstrated that elderly women tolerate pelvic radiotherapy and brachytherapy well. It was reported that el-derly patients get equivalent survival to young patients when treated with definitive RT. A propensity-matched score analysis in Taiwan by Wang Y et al. showed no signif-icant differences in cancer-specific survival, local and distant failure rates between the elderly group (≥75 years), and young group (<60 years), although OS was inferior in the elderly. The 5-year OS in the elderly group was 49.2%.[32]
Another retrospective analysis by Yoshida K et al. evaluated survival outcomes in 40 Japanese women of age 75 years or more re-ported 3-year overall and disease-specific sur-vival of 58% and 80%, respectively.[33] In the current study, the 5-year OS was 54.9% and DFS at 3 years and 5 years were 66.3% and 45.9% respectively.
Table 5 shows various published literature evaluating the treatment outcome of elderly Table 5
Tr ea tmen t out come of elder ly pa tien ts with c er vix canc er tr ea
ted with definitiv
e R
adiother
ap
y with or without chemother
ap
y fr
om v
ar
ious published lit
er at ure Study Study design A ge gr oup Numb er of M edian age Tr ea tmen t M edian f ollo w -up O ut come pa tien ts (R ange) M odalities (R ange) Yoshida K et al .[33] Retr ospec tiv e ≥75 y ears 40 78 y ears D efinitiv e R T ±C C T 20 mon ths 3 y ear OS 58% analy sis (75–89) (1–85) 3 y ear DSS 80% Ying G ao et al .[36] Retr ospec tiv e <65 y ears 52 49.2 y ears D efinitiv e R T ±C C T 36.5 mon ths <65 y ears: OS 73.1%, DFS 71.2% analy sis ≥65 Year 107 (21–78) ≥65 Year : OS 72.9%, DFS 67.3% H ideyuk i S ak ur ai et al .[37] Retr ospec tiv e <70 y ears 215 D efinitiv e R T ±C C T <70 y ears: 5 y ears OS 58% analy sis 70-79 y ears 124 70-79 y ears: 5 Year OS 50% ≥80 y ears 41 ≥80 y ears: 5 Years OS 33% M ing Yin Lin et al .[38] Retr ospec tiv e ≥75 y ears 126 M ean 81.5 D efinitiv e R T ±C C T 37 mon ths 3 and 5 y ear : OS 52.7%, 41.2% analy sis (SD 4.6) A djuv an t R T ±C C T (10.5 t o 71.1) for en tir e c ohor t Pallia tiv e R T W ang W et al .[34] Retr ospec tiv e ≥70 y ears 73 74 y ears D efinitiv e R T ±C C T 32.4 mon ths The 3-year OS 64.9%, analy sis (70-88) (4.8–118.8) The 3-year DFS 66.5% for the en tir e c ohor t W ang W et al .[22] Retr ospec tiv e Young <60 991 49 (23-59) D efinitiv e R T ±C C T 30.2 mon ths <60 y ears: 3 Year OS, analy sis Old >70 70 74 (70-88) (1.9-93.0) DFS 86.5%, 74.6% >70 y ears: 3 y ear OS, DFS 73.9%, 75.4% Pr esen t study* Retr ospec tiv e 75 y ears or mor e 23 77 y ears D efinitiv e R T ±C C T 46 mon ths OS a t 5 y ears and 7 y ears analy sis (75-85) (3-93) 54.9% and 43.9% DFS a t 3 y ears and 5 y ears 66.3% and 45.9% *R esults of the pr esen t study , C C T: C oncur ren t chemother ap y; OS: O ver all Sur viv al; DSS: disease -specific sur viv al; DFS: Disease -fr ee sur viv al .
Conclusion
The number of elderly patients with cervical cancer is increasing and definitive radiotherapy gives good treat-ment outcomes with acceptable toxicity. However, cau-tion should be taken when more aggressive treatment modalities like CCRT are used. In our study, good sur-vival outcome with acceptable early and late treatment-related toxicity was observed. It can be concluded that definitive radiotherapy is well tolerated by elderly pa-tients and should be considered whenever feasible.
Peer-review: Externally peer-reviewed.
Conflict of Interest: On behalf of all authors, the
corre-sponding author states that there is no conflict of interest.
Ethics Committee Approval: The study was approved by
Institutional Ethics Commitee; BBCI Medical Ethics Com-mittee (Registration No: ECR/1040/Inst/AS/2018), vide approval letter Ref No. BBCI-TMC/Misc-01/MEC/71/2019 Date 27th July 2019.
Financial Support: This research did not receive any
spe-cific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Authorship contributions: Concept – G.S.; Design – G.S.,
J.N.; Supervision – A.K.K.; Funding – None; Materials – L.B., J.N.; Data collection and/or processing – L.B., J.N.; Data analysis and/or interpretation – J.N., G.S.; Literature search – P.P.M., G.S., J.N.; Writing – J.N., G.S.; Critical review – M.B. References
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Limitations
The current study has many limitations. Firstly, it is a retrospective study and the study population is het-erogeneous. Further, the sample size was small and the EBRT in our patients was delivered with a conven-tional technique. None of the patients received Cisplat-in-based concurrent chemotherapy. Therefore, further research in elderly patients with cervical cancer in a prospective design with a larger sample size needs to be done.
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